2-Halo-1-(alkyl-1-(alkylamino) ethyl) vinyl alkanoic esters and derivatives

ABSTRACT

2-Halo-1-(alkyl-1-(alkylamino) ethyl) vinyl alkanoic esters and derivatives, useful as intermediates in the preparation of Alpha -halo- Alpha , Alpha -disubstituted amino ketones.

United States Patent 1191 Easton et al.

[ Z-HALO-I-[ALKYL-l-(ALKYLAMINO) ETHYL] VINYL ALKANOIC ESTERS AND DERIVATIVES [75} Inventors: Nelson R. Easton; William W.

Hargrove, both of lndiunzipolis, Ind

[73] Assignee: Eli Lilly and Company, Indianapolis Ind.

1221 Filed: June 3. 1974 121 Appl. N0; 475,722

Related [1.8. Application Data [60] Continuation-impart of Ser. No. 321.426. Jun 1. 1973 Pat No 31839 4l5 which is 11 division of 501' No. 5527043 May 22 1969. which is u continuation-impart of Sen No. 502.359, Oct. 22,

I965 abandoned [52] US. Cl. 260/468 R; 260/307 F; 260/490; 260/558 R; 260/56l R; 260/562 R; 260/563 C; 260/5705 C; 260/5708 R; 260/576;

' 14 1 Sept. 16, 1975 ASS/SIGN! Elt'mninM-E Jane Skelly AIIUHH), Agent, or Firm.lumes Lv Rowe; Evcret F. Smith [57] ABSTRACT 2-H11lol-[11lkyl-l-(alkylumino) cthyll vinyl Zllkill'lOlC esters and derivatives useful as intermediates in the preparation of oz-halomr a-disuhstitutcd amino ketones.

1 Claim. No Drawings 2-HALO- l ALKYL- l ALKYLAMINO) ETHYL) VINYL ALKANOIC ESTERS AND DERIVATIVES CROSS-REFERENCE This application is a continuation-in-part of our copending application. Ser. No. 32l,426, filed .lan. l, I973, now US. Pat. No. 3,839,4l which application was a division of our eopending application Ser. No. 827,043 filed May 22, I969, which application was a eontinuationin-part of our then copending application Ser. No. 502,359, filed Oct. 22, 1965, now abandoned.

BACKGROUND OF THE INVENTION a-Halo a,a-disubstituted a-amino ketones are useful as intermediates in the synthesis of a,a-disubstituted azetidonones, as set forth in the copending applications of William W. Hargrove, Ser. No. 502,331 filed Oct. 22, 1965, now US. Pat. No. 3,48l,920 and Ser. No. 790,852, filed Jan. 13, l969, now US. Pat. No. 3,494,964.

A synthesis of a'-halo a,a-disubstituted a-amino ketones is described in US. Pat. No. 3,481,920. According to this synthesis the desired product is obtained by treating a glacial acetic acid solution of the amino ketone with the appropriate halogen. The product is isolated in the form of the acid addition salt of Formula I. This simple, convenient, and easily performed preparation has been found to possess certain limitations. e.g., in those compounds where R represents a monophenyl-substituted lower alkyl group, halogenation appears to occur in the alkyl portion of said group.

It is an object of the invention to provide a method of obtaining a-halo a,a-disbustituted a-amino ketones, which method avoids the undesirable aspects of previous methods.

SUMMARY This invention relates to a novel process for preparing a'-halo a,a-disubstituted a-amino ketones and to intermediates useful in that process.

The novel process provided by this invention comprises the halogenation of an acylamidoacetylene in an inert solvent to yield an oxazolinium derivative. Treatment of the oxazolinium salt with water produces di rectly the enolate of an oz'-halo a,a-disubstituted a-amino ketone, which enolate, upon treatment with acid. ketonizes to yield the desired a-halo a,a-disubstituted a-amino ketone. This process is more graphically illustrated with reference to Reaction Sequence I below.

REACTION SEQUENCE I R and R when taken separately, are C C; alkyl, C -,C, cycloalkyl, or phenyl;

R and R when taken together with the carbon atom to which they are attached, represent C -C cycloalkyl;

R is hydrogen, C,C r, alkyl, C C cycloalkyl, phenyl, or phenyl-substituted C C, alkyl;

R is hydrogen or C C; alkyl;

R is C -C alkyl, C -C cycloalkyl, phenyl, halosubstituted phenyl or phenyl-substituted C -C alkyl; and

X is bromine, chlorine, or iodine.

In the above formulas, C,-C,, alkyl can be illustratively methyl, ethyl, isopropyl, n-propyl, sec'amyl, sec.-butyl, t-butyl, n-amyl, isobutyl, isoamyl, 3-methyl- 2-butyl, 2-methyl-2butyl, Z-pentyl, 3-pentyl, neopentyl, and the like.

C -,C.,- cycloalkyl" can be cyclohexyl or cyclopentyl.

C C cycloalkyl can be illustratively cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl. methyl-cyclopentyl, cthylcyclohexyl, and the like.

C,C;, alkyl" can be methyl, ethyl, n-propyl. and isopropyl.

Representative phenyl-substituted C,-C;, alkyl radicals are benzyl. 2'phenethyl. 2-phenylpropyl 3- phenylpropyl, l-phenylethyl, and the like.

The term halo-substituted phenyl" includes a phenyl radical substituted with one or more halogen atoms such as o-chlorophenyl, p-iodophenyl. m fluorophenyl, 2-chloro 4-bromophenyL 2.4.5- trichlorophenyl, and the like. According to the novel process of the instant invention, a solution of acylamido acetylene (l) in an inert solvent is treated with the desired halogen. Suitable inert solvents include chloroform, ether, dioxane, methylene dichloride, dichloroethane, dimethyllormamide, and the like. The halogenation reaction is spontaneous, the reaction mixture becoming warm, and the halogen color disap pearing without the necessity of external heating. Some of the oxazolinium salts (ll) thus formed are sufficiently insoluble in the reaction mixture to precipitate immediately as the reaction proceeds and can be conveniently recovered by filtration. Others are more solu ble. and it is necessary to concentrate the reaction mix tures in order to cause the oxazolinium salt to precipitate. The structures of the oxazolinium salts have been determined and assigned through the use of elemental analyses and infrared and nuclear magnetic resonance (n.m.r.) spectra.

Conversion of the oxazolinium salts to the enol estcrs, (III) is accomplished by treating the oxazolinium salt with a mixture of acetone and water. concentrating the reaction mixture to dryness, and recrystallizing the residue from a suitable solvent. However. in some cases the oxazolinium salt is sutficiently unstable to undergo rapid conversion to the enol ester merely on standing Structures of these enol esters have also been confirmed by elemental and spectral analysis.

Hydrolysis of the enol esters using strong acids in aqueous solution yields the desired a'-halo mwdisubstituted a-amino ketoncs, which are obtained in the form of their acid addition salts. Strong acids suitable for use in this hydrolysis include hydrochloric. hydrobromic. and hydriodic acids.

The acylamido acetylenes (I) wherein R and R are C,C;, alkyl employed as starting materials in our novel process can be prepared by the method of Easton ct. al..J. Org. Chem. 28. 2465 1963). utilizing aminoace tylenes synthesized by the methods of Hennion and Hanzel. J. Am. Chem. Soc. 82. 4908 1960). or of Eas ton et al.. J. Org. Chem. 26. 3772 196] Starting materials wherein R or R is phenyl are prepared by the process described in Easton et al. in J. Org. Chem. 27. 2746 1962). i

The a'-halo a.oz-disubstituted oz-amino ketones preparable by the process of this invention are useful intermediates in the preparation of 2.2-disubstituted-3 azetidinones. which compounds are disclosed in the copending application of William W. Hargrove. Ser. No. 502.331. filed Oct. 22. I965. now U.S. Pat. No. 3.481 .926. These latter 3-azetidinones have interesting hypotensive activity. ln addition, they serve as intermediates in the preparation of the corresponding 3- axetidinols and axetidines. The azetidinols possess CNS stimulant properties and the azetidiones are blood pres sure-lowering agents. The hypotensive properties of the 3azetidinones preparable from the compounds of this invention can be utilized by administering 3- azetidinones in a composition adapted for oral or parenteral administration, oral administration beng especially preferred because of the case and convenience associated therewith. Thus. the 3-azetidinones can be administered in the form of a compressed tablet or a filled capsule. as well as in the form of a solution or suspension suitable for oral or intramuscular administration. The hypotensive activity of the 3-azetidinones is shown when they are administered orally to rats made hypertensive by the well-known Goldblatt method. Doses of 20-40 nag/kg. orally cause a significant lowering of the blood pressure in the test animals.

The 3a7.ctidinols and azctidines preparable from the said 3-azetidinones possessing CNS stimulant properties can be utiliyed by administration in a form adapted for intraperitoneal administration. Thus. they can he in the form of a solution or suspension suitable for intra'peritoncal administration. The CNS stimulant prop erties are shown when the compounds are administered intra-peritoneally to mice is doses of l-l00 mg./kg. These dosages produce an increase in the rate ol'respiration. some vasodilatation, and an increased irritabilily of the test animals.

The oxazolinium salts and cnol ester acid addition salts. Formulas II and Ill. respectively. are useful intermediates in the preparation of the above u'-halo a.a-disuhstituted wamino ketones preparable by the process of this invention.

The invention is more clearly described by the fol lowing operating examples. which are not intended to limit the scope thereof in any way.

EXAMPLE l 2.3 .4.4 letramethyl-5-( bromomethylene )-2 oxazolinium bromide A solution of g. of 3-methyl-3-(N-acetyl-N- methyl)-aminol-butyne in 200 ml. of chloroform was treated with 23 g. of bromine dissolved in 50 ml. of chloroform. The solid which separated was filtered ofi and recrystallized from isopropyl alcohol to yield 38 g. of 2.3 .4.4-tetramethyl5-( bromomethylene )-2- oxazolinium bromide having a melting point of about 225227 C. It was identified by elemental analysis and by infrared and n.m.r. spectra.

Analysis Calcd: C. 32. I3: H. 4.38. Found: C. 32.371H. 4.49.

Using the same procedure as described in Example 1, the following compounds were prepared:

2 .4.4 .4-Trimethyl-5 bromomethylene )-2- oxazolinium bromide. Melting Point: l88-l90 C.

Analysis Calcd: C, 29.50; H. 3.89. Found: C, 29.64; H, 3.89.

Z-(p-Chlorophenyl )-3,4.4-trimethyl-5-( l -bromoethylidene)-2-oxazolinium bromide. Melting point: 225227 C.

Analysis Calcd: C, 4l.05; H. 3.93. Found: C, 4l.OO; H. 4.20.

2-( 3,4Dichlorophenyl )-3-methyl-4.4 pentamethylene-5-( bromomethylene )-2-oxazolinium bromide. Melting Point: 233-234 C.

2-( 2,4-Dichlorophenyl )-4.4-pentamethylene-5- (bromo-methylene)-2-oxazolinium bromide. Melting point: 128l29 C.

Analysis Calcd: C. 39.50: H. 3.3 I. Found: C. 39.10: H. 3.48.

2.3.4,4-Tetramethyl-5-(chloromethylene)-2- oxazolinium chloride was obtained and identified by means of infrared and n.m.r. spectra.

3 .4.4-Trimethyl-5-( chloromethylene )-2-oxazolinium chloride. Melting point: l62l64 C. Identified by means of infrared and n.m.r. spectra.

2.3.4,4"l"etramethyl-5-( l-bromoethylidene )-2- oxazolinium bromide. Melting point: 2l922l C.

Analysis Calcd: C. 34.53; H. 4.82. Found: C. 34.40; H. 4.76.

2,3Dimethyl 4.4-pcntamethylene-5-( bromomethylene)-2-oxazolinium bromide. Melting point: 20b208 C.

Analysis Calcd: C. 38.96; H. 5.05. Found: C. 38.82; H. 5.60.

3.4.4-'lrimethyl-5-( bromomethylene l-2-oxazolinium bromide. Melting point: 205206 C. with decomposition.

Analysis Calcd: C. 29.50: H. 3.89. Found: C. 29.39; H. 4.18.

2.4-DimethyL4-sec.-butyl-5-( bromomethylene )-2- oxazolinium bromide. Melting point: l200 C. with decomposition.

Analysis Calcd: C. 36.72; H. 5.23. Found: C. 36.29: H. 5.36.

2.4-Dimethyl-4-isopropyl-5-( bromomethylene )-2- oxazolinium bromide. Melting point: l87-l 89 C. with decomposition.

Analysis Calcd: C. 34.53; H. 4.82. Found: C. 34.7l; H. 5.05.

2-( 3.4-Dichlorophenyl )-3.4.4-trimethyl-5- (bromomethylene )-2-oxazolinium bromide. point: 24024l C.

Analysis Calcd: C. 36.3l: H. 3.04. Found: C. 42.23; H. 4.34.

2-( p-Chlorophenyl )-3 .4.4-trimethyl-S-( iodomethylene )-2-oxazolinium iodide. Melting point: 2 l4-2 16 C.

Analysis Calcd: C. 31.89; H. 2.88. Found: C. 32.07; H. 2.80.

Melting EXAMPLE 2 l-Chloro-N,3-dimethyl-2-(2,4-dichlorobenzolyloxy l butenyl-3-amine hydrochloride To a solution of 10 g. of 3-(N-methyl-2,4- dichlorobenzamido )-3-methyl-l-butyne in chloroform was added a solution of l g. of chlorine in chloroform dropwise until a yellowish color persisted. The solution was evaporated to dryness in vacuo and the residue recrystallized from ethyl acetate to yield l-chloro-N,3- dimethyl-2-( 2,4-dichlorobenzoyloxy, l -butenyl-3- amine hydrochloride in the form of a solid having a melting point of about l98l99 C.

Analysis Calcd: C, 43.48; H, 4.21. Found: C, 43.30; H, 4.32.

Using the same procedure as described in Example 2, the following compounds were prepared:

l 2-Chlorol 2,4-dichlorobenzoyloxy )vinyl l-N- methyl-cyclohexylamine hydrochloride. Melting point:

1 l6l 17 C.

Analysis Calcd: C, 48.14; H, 4.80. Found: C, 47.6l; H, 4.84.

l-[2Chloro-l-(3,4-dichlorobenzoyloxy)vinyll-N- methyl-cyclohexylamine hydrochloride. Melting point:

l97-l98 C.

Analysis Calcd: C, 48.14; H, 4.80. Found: C, 48.49; H, 4.65.

l-[ Z-Chlorop-ehlorobenzoyloxy )vinyl |-N-meth yl-cyclohexylamine hydrochloride. Melting point: 9596 C.

Analysis Calcd: C, 52.98; H, 5.00. Found: C, 52.93; H. 5.16.

l-Bromo-N,3-dimethyl-2-(p-chlorobenzoyloxyl-lbutenyl-3-amine hydrobromide. Melting point: l94l96 C.

Analysis Calcd: C, 37.75; H, 3.90. Found: C, 38.l l; H, 4.12.

lBromo-N,3dimethyl-2-(2,4-dichlorobenzoyloxy)- l-butenyl3-amine hydrobromide. Melting point: l62l63 C.

Analysis Calcd: C, 34.85; H, 3.37. Found: C, 34.95; H, 3,26.

l-l2-Bromo-l-(2,4-dichlorobenzoyloxy)vinyl]N- methyl-cyclohexylamine hydrohromide. Melting point: 174-l75 C.

Analysis Calcd: C, 39.37; H, 3.92. Found: C, 39.29; H, 4.17.

EXAMPLE 3 ]-Bromo-N,3-dimethyl-2-( 3,4-dichlorobenzoyloxy l butenyl-3-amine hydrobromide 5 g, of 2-(3,4dichlorophenyl)-3,4,4-trimethyl-5- bromomethylene-Z-oxazolinium bromide were dissolved in a mixture of l00 ml. of acetone and L0 ml.

of water. The solution was evaporated in vacuo and the residue recrystallized from methyl ethyl ketone to yield 5 g. of l-bromo-N,3-dimethyl-2-( 3 ,4- dichlorobenzoyloxy l -butenyl-3amine hydrobromide having a melting point of about l80 C. (dee).

Analysis Calcd: C, 34.85; H, 3.37. Found: C, 35.06; H. 3.67.

Additional compounds prepared by the above procedure include:

l-l l 3,4 Dichlorobenzoyloxy )-2-bromovinyl ]-N- methyl-eyclohexylamine hydrobromide. Melting point: l82 C. (dee).

Analysis Calcd: C, 39.37; H, 3.92. Found: C, 39.1 l; H, 4.04.

l l 2,4-Diehlorobenzoyloxy )-2-bromovinyl l-N- methyl-cyclohexylamine hydrobromide. Melting point: l62l63 C.

Analysis Calcd: C, 39.37; H, 3.92. Found: C, 39.41; H, 4.07.

l-Bromo-N,3-dimethyl-2-( 2,4-dichlorobenzoyloxy l-butenyl-3-amine hydrobromide. Melting point: 180 C. (dec.).

Analysis Calcd: C, 34.85; H, 3.37. Found: C, 34.95; H, 3.26.

l-Chloro-N,3-dimethyl-2-( 2,4-dichlorobenzoyloxy l-butenyl-3-amine hydrochloride. Melting point: l98l99 C.

Analysis Calcd: C, 43.48; H, 4.21. Found: C, 43.30; H, 4.23.

l 1-( 2,4-Dichlorobenzoyloxy l -chlorovinyl l-N- methyl-cyclohexylamine hydrochloride. Melting point: I l6l l7 C.

Analysis Calcd: C, 48.l4; H, 4.80. Found: C, 47.6l; H, 4.84.

l-{ l( 3,4-Dichlorobenzoyloxy l -chlorovinyl ]-N methyl-cyclohexylamine hydrochloride. Melting point: l97-l 98 C.

Analysis Calcd: C, 48.14; H, 4.80. Found: C. 48.49; H, 4.65.

l Bromo-N,3-dimethyl-2-( 3,4-diehlorobcn2oylox) l-butenyl3 amine hydrohromide. Melting point; 180 C. (dec.).

Analysis Calcd: C, 34.85; H, 3.37. Found: C. 35.06; H. 3.67.

l ,[2-Bromo l-( 3,4-dichlorobenzoyloxy )vinyl I-N- methyl-cyclohexylamine hydrohromide. Melting point: l82 C. (dec.

Analysis Calcd: C, 39.37; H, 3.92. Found: C, 39.1]; H, 404.

EXAMPLE 4 l -Bromo-3 ,4-dimethyl-3-amino-2-pentanone hydrobromide A solution was prepared ol' 2,4-dimethyl-4-isopropyl- 5-(bromomethylenel-2-oxazolinium bromide in ethanol and allowed to stand at room temperature. The solvent gradually evaporated and the solid residue was recrystallized from ethanol to yield lbromo-3,4 dimethyl-3amino-Z-pentanone hydrobromide having a melting point of about ]58-l60 C. The material was identified by the n.m.r. spectrum.

EXAMPLE 5 3-Methyl-3-( B-phenethylamino l -hromo-2-butanone hydrobromide A solution of l0 g. of 3-methyl-3(N-lormyl-N-fi phenethyl)aminol-butyne in ml. of chloroform was prepared, and to the solution were added 100 ml. of methanol and 8 g. of bromine in chloroform dropwise with stirring. After addition was complete, the solvent was removed in vacuo and the residual oil was dissolved in isopropanol. The solid product which crystal lized out was identified as 3-methyl-3-( B- phenethylamino 1 bromo-2-butanone hydrobromide, a solid having a melting point of about l62-l63 C. with decomposition. The analysis indicates the crystalline compound obtained to be an alcoholate composed of one mole of the amino ketone plus one mole of iso propanol.

Analysis Calcd: C. 45.l9; H. 4.60 Found: C. 45. l 7: H. 4.80.

EXAMPLE 6 l -chloroacetyl-N-methylcyclohexylamine A solution was prepared of 2U g. of 3- pentamethylene-3-( N-methyl-N-formyl l -propyne in a mixture of chloroform and ether. Gaseous chlorine was bubbled into the mixture until no more solid was formed. During the introduction of the chlorine gas. the mixture became warm and quite viscous. and more chloroform was added to facilitate stirring.

The excess solvent was removed at reduced pressure and the residual solid recrystallized from a mixture of isopropyl alcohol and ether. to yield l-chloroacetyl-N methylcyclohexylamine hydrochloride as a solid having a melting point at about l52-l54 C. The compound was identified by means of the n.m.r. spectrum and ele mental analysis.

Analysis ('alcd: C. 47.80; H. 7.57. Found: C. 48.60; H. 7.73.

EXAMPLE 7 Z-Metbyl-4.4-pentamethylene-5-bromomethylene-Z- oxazolinium bromide To a solution of 66 g. of 3-pentamethylene3(N acetyl)lpropyne in 100 ml. of dimethyltormamide was added a solution 0f 30 g. of silver nitrate in 50 ml. of dimethylformamide and the mixture stirred for about 3 hours at a temperature of about (AP-80 C. 'l he reaction product mixture was cooled and diluted with saturated aqueous sodium chloride solution and e\- traeted with methylene dichloride. The organic layer was separated. washed with water. dried. and distilled to yield material having a boiling point of about (15 at 3 mm. The material was identified by n.m.r. as Z- methyl4.4-pentamethylene-imethylene-Z-oxa/ole and was used without further purification in the sac ceeding step of the preparation.

The crude product front above. 16.5 g. was dissolved in SUU ml. of anhydrous methylene dichloride and maintained under a nitrogen atmosphere while 55 ml. of bromine was added dropwise to the solution until the bromine color no longer disappeared. The reaction product mixture was maintained in a nitrogen atmosphere and stirred at ambient room temperature over the weekend. After about l d hours. a solid crystalline product began to appear. The reaction product mixture was filtered and the solid material. which had a melting point of about l98-2ll4('.with decomposition. was identified by its elemental analysis and infrared and n.m.r. as Zanethyl4.4-pentamethylene5- hromomcthylcne-loxa/olinitlm bromide.

Analysis Caled; (I 36.95: H. 4.65: N. 4.3 I. Found: 3715; H. 4.t1l: N. 4.32.

Following the above procedures:

Nben/oyl-Nphenethyl 3-amino 3 mcthyl butync can be chlorinated to yield Z-phenyl-3-phenethyl -L-l dimethyl-5-chlonmiethylenc ovavolinium chloride. Re action of this latter compound with water yields 1- ChlUt'tFN-PhCl1ClhYl 3 fllClhl-2l7L.H/U}lti\} 3 aminol butene hydrochloride. treatment of which with acid spectra gives 3-phenethylamino3-methyll-chloro-2- butanone N-formyl-N-t 2-pentyl l-aminol -ethinylcyclopentane can be brominated to yield 3-( l-pentyl)-4.4- tctramethylene-S-bromomcthylene oxazolinium bromide. Reaction of this latter compound with water yields l-( l-formyloxy-2-chlorovinyl l Z-pentylamino)-cyclopentane hydrobromide. treatment of which with acid gives l-( w-bromoacetyl l methylamino cyclopentane.

N-Z,4-difluorobenzyl-N-n-butyl-4-amin0-4-ethyl-2- hexyne can be iodinated to yield 2( 2.4-difluorophenyl 3-n-butyl-4.4-diethyl-5-iodoethylidene oxazolinium iodide. Reaction of this latter compound with water yields l -iodo-N-n-butyl-2-( 2.4-diflu0roben2oyloxy )-4- ethyl-4-amino-2-hexenc hydroiodide. treatment of which with acid yields 4-n-butylamino-4-ethyl-2-iodo- 3hexanone.

Other a-halo-oz.a-disubstituted-a-amino ketones preparable by the processes of this invention include1 3-methyl-3-methylamino l-bromo2butanone 3-methyl-3-methylamino- Lchloro-B-pentanone 3-methyl 3-n propylaminol chloroJ-pentanone l-bromoacetyl-N-methyleyclohexy lamine hydrobromide 3-methyl-3-ethylaminol-bromo-2-pentanone 3-methy l 3-ethylarninol -chloro- Z-n-heptanone hydro chloride 4-ethylLn-butylamino-2 bromo3n-heptanone 3-phenyl-3 phenethylamino l bromo lbutanone 3-phenyl-3-( phcny lamino ll -bromol butanone 4phenyl 4-phenylaniino-Ibromo f -hexanone 3*cthyl'3-cyclohexylamino-l-chloro-Z-pentanone 4-niethyl-3-cyclopropylamino-ZbromwB-heptanone l-iodoacetyl-N-methylcyclohexylamine hy driodide Other otazolinium salts preparable by the processes of this invention and useful as intermediates therein include:

It m-bromophenyl l-3-t l-penty l ]--1 cy clopentyl-4-phe nyfichloroniethylene oxazolinium chloride Z.B-dicyclohexyl -lA diphenyl 5chloropropylidene ox a/olinium chloride l t 3-m-bromtiphenylpropyl l3npropy l--l.4-di-n-pro pyl 5-bromomethylene oxarolinium bromide 2-cyelopentyl-3-eyclobutyL-Lphenyl-Jmethyl-5- iodomethylene o\a7olinium iodide Z-n-buty l-3'I Z-phenylpropyl l*4-methyl-4-cyclopentyl- S-t l-iodoethylidene )outzolinium iodide 3-cyclooctyl-4-methyl-4isopropyl-5- bromopropylidene ovayolinium bromide.

Other enolacylates of cx-amino ketones useful as in termediates in the processes of this invention include: 3-chloro-5-t mbromophen lamino )-5-phenyl-5* cyelopentyl-4-n-caproyloxylpentene l-chloro 3cyclohexylamino-Ti.3-di-phenyl-2- ey elohesy lcarboxy 1 -propene N 3-m bromopheny lpropyl l-3-amino-3-n-propy lZ-n butyro\yl he\ene liodo-3-cyclopenty lamino-3-pheny l cyclopentylearboxy l-butene Z-iodo-4-ti-bttt) lamino4-c clopenty l3( 2- phenylpropionoxy )-2-pentene lt tll SfllllllliU-SFklllllClh)l hC)ClUUCi}lUtlI'hU\}-3 heptene. We claim: I. A compound of the formula H R and R when taken together with the carbon atom R1' NH to which they are attached. represent C ,C.; cycloalkyl' R-(--C=(R* R" IS hydrogen. C -C ulkyl. C C cycloalkyl, phenyl, R X 5 or phenyl-substituted C -C ulkyl;

R is hydrogen or C,C,-, alkyl; wherein R is hydrogen. C C alkyl. or C -C cycloalkyl; and R and R". when taken sep ra ely. r 1- 5 l y X is bromine. chlorine, or iodine.

C .-,C cycloalkyl, or phenyl; m 

1. A COMPOUND OF THE FORMULA 